A Pharmacometric Framework for Axitinib Exposure, Efficacy, and Safety in Metastatic Renal Cell Carcinoma Patients
| Autor: | Schindler, Emilie, Amantea, Michael A, Karlsson, Mats O, Friberg, Lena E |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Vascular Endothelial Growth Factor A
Indazoles Vascular Endothelial Growth Factor Receptor-1 Axitinib Imidazoles Antineoplastic Agents Blood Pressure Original Articles Kaplan-Meier Estimate Farmaceutiska vetenskaper Vascular Endothelial Growth Factor Receptor-3 Models Biological Vascular Endothelial Growth Factor Receptor-2 Kidney Neoplasms Tumor Burden Pharmaceutical Sciences Proto-Oncogene Proteins c-kit Treatment Outcome Biomarkers Tumor Humans Original Article Carcinoma Renal Cell Protein Kinase Inhibitors |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology |
| ISSN: | 2163-8306 |
| Popis: | The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. (ClinicalTrial.gov identifier NCT00569946.). |
| Databáze: | OpenAIRE |
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